rs199472679

chr11-2445442-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):c.344A>G(p.Glu115Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E115K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.38

Genes affected

KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2445441-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200879.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-2445442-A-G is Pathogenic according to our data. Variant chr11-2445442-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2445442-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.344A>G	p.Glu115Gly	missense_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1	c.344A>G	p.Glu115Gly	missense_variant	1/15
KCNQ1	NM_001406838.1	c.344A>G	p.Glu115Gly	missense_variant	1/11
KCNQ1	NM_001406837.1	c.-19A>G		5_prime_UTR_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.344A>G	p.Glu115Gly	missense_variant	1/16	1	NM_000218.3	P1
KCNQ1	ENST00000345015.4	n.121A>G		non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7	c.83A>G	p.Glu28Gly	missense_variant	2/16	5
KCNQ1	ENST00000646564.2	c.344A>G	p.Glu115Gly	missense_variant	1/11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 115 of the KCNQ1 protein (p.Glu115Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 15840476; Invitae). ClinVar contains an entry for this variant (Variation ID: 53037). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 29532034, 30571187). This variant disrupts the p.Glu115 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been observed in individuals with KCNQ1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2019

The p.E115G variant (also known as c.344A>G), located in coding exon 1 of the KCNQ1 gene, results from an A to G substitution at nucleotide position 344. The glutamic acid at codon 115 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a long QT syndrome (LQTS) cohort with limited clinical information (Tester DJ et al. Heart Rhythm. 2005;2:507-17). In vitro functional analysis suggests this variant results in significantly reduced channel current and a dominant negative trafficking defect (Huang H et al. Sci Adv. 2018;4:eaar2631). Internal structural analysis indicates that this variant interacts with residues of known function and is more disruptive than known pathogenic variants in the region (Ambry internal data; Berman HM et al. Acta Crystallogr. D Biol. Crystallogr. 2002;58:899-907). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	.;D
Vest4		0.92
MutPred		0.88		.;Gain of MoRF binding (P = 0.0382);
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.91
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199472679; hg19: chr11-2466672; COSMIC: COSV104380888; COSMIC: COSV104380888;